Lung mechanics modifications facilitating metastasis are mediated in part by breast cancer-derived extracellular vesicles.

Tumor microenvironment-mechanics greatly affect tumor-cell characteristics such as invasion and proliferation. We and others have previously shown that after chemotherapy, tumor cells shed more extracellular vesicles (EVs), leading to tumor growth and even spread, via angiogenesis and the mobilization of specific bone-marrow-derived cells contributing to metastasis. However, physical, mechanobiological and mechanostructural changes at premetastatic sites that may support tumor cell seeding, have yet to be determined. Here, we collected tumor-derived extracellular vesicles (tEV) from breast carcinoma cells exposed to paclitaxel chemotherapy, and tested their effects on tissue mechanics (eg, elasticity and stiffness) of likely metastatic organs in cancer-free mice, using shear rheometry. Cancer-free mice were injected with saline or with tEVs from untreated cells and lung tissue demonstrated widely variable, viscoelastic mechanics, being more elastic than viscous. Contrastingly, tEVs from chemotherapy-exposed cells induced more uniform, viscoelastic lung mechanics, with lower stiffness and viscosity; interestingly, livers were significantly stiffer than both controls. We observe statistically significant differences in softening of lung samples from all three groups under increasing strain-amplitudes and in their stiffening under increasing strain-frequencies; the groups reach similar values at high strain amplitudes and frequencies, indicating local changes in tissue microstructure. Evaluation of genes associated with the extracellular matrix and fibronectin protein-expression revealed potential compositional changes underlying the altered mechanics. Thus, we propose that tEVs, even without cancer cells, contribute to metastasis by changing microstructures at distant organs. This is done partially by altering the composition and mechanostructure of tissues to support tumor cell invasion and seeding.

Sodium pyruvate pre-treatment prevents cell death due to localised, damaging mechanical strains in the context of pressure ulcers.

We demonstrate sodium pyruvate (NaPy) pre-treatment as a successful approach for pressure ulcer (PU) prevention by averting their aetiological origin-cell-level damage and death by large, sustained mechanical loads. We evaluated the NaPy pre-treatment effect on permeability changes in the cell's plasma membrane (PM) following application of in vitro damaging-level strains. Fibroblasts or myoblasts, respectively, models for superficial or deep-tissue damage were grown in 0 or 1 mM NaPy, emulating typical physiological or cell culture conditions. Cells were pre-treated for 4 hours with 0 to 5 mM NaPy prior to 3-hour sustained, damaging-level loads (12% strain). PM permeability was quantified by the cell uptake of small (4 kDa), fluorescent dextran compared with unstrained control using fluorescence-activated cell sorting (FACS). Pre-treatment with 1 mM, and especially 5 mM, NaPy significantly reduces damage to PM integrity. Long-term NaPy pre-exposure can improve protective treatment, affecting fibroblasts and myoblasts differently. Pre-treating with NaPy, a natural cell metabolite, allows cells under damaging-level mechanical loads to maintain their PM integrity, that is, to avoid loss of homeostasis and inevitable, eventual cell death, by preventing initial, microscale stages of PU formation. This pre-treatment may be applied prior to planned periods of immobility, for example, planned surgery or transport, to prolong safe time in a position by preventing initial cell damage that can cascade and lead to PU formation.

T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. SIGNIFICANCE: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.See related commentary by Kolonin and Woodward, p. 197.